MLL3/MLL4 are H3K4me1/2 methyltransferases enriched on enhancers. CBP/p300 are H3K27 acetyltransferases enriched on active enhancers. How these epigenomic writers orchestrate enhancer activation during cell differentiation is incompletely understood. We have profiled transcriptome, epigenome, and genomic binding of MLL4, CBP and lineage-determining transcriptional factors (TFs) during adipogenesis of brown preadipocytes. We show that dynamic epigenome correlates with dynamic transcriptome and that MLL4 and CBP drive the enhancer epigenome. Further, MLL3/MLL4 facilitate chromatin opening and CBP/p300 binding on enhancers activated during adipogenesis. Analysis of MLL4 and CBP binding identifies EBF2 as a pioneer TF that binds to general adipogenic enhancers. Finally, MLL4 and CBP identify super-enhancers associated with cell identity genes. In preadipocytes, MLL4 pre-marks a subset of super-enhancer constituents; in adipocytes, MLL4 identifies primed super-enhancers of genes fully activated in brown adipose tissue such as Ucp1. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers that sequentially shape the dynamic enhancer landscape in adipogenesis. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis. SOURCE: Kai Ge (kai.ge@nih.gov) -  NIH

Pluto Bioinformatics

GSE74189: Master epigenomic writers MLL4 and CBP shape dynamic enhancer landscapes in adipogenesis